The present invention provides combination therapy for the treatment of benign prostatic hyperplasia. More particularly, the combination comprises an alpha-1a adrenergic receptor antagonist with an endothelin antagonist, and optionally a 5a-reductase inhibitor, for relief of lower urinary tract symptoms in patients with symptomatic prostatism or benign prostatic hyperplasia.
Benign prostatic hyperplasia, also known as benign prostatic hypertrophy or BPH, is an illness typically affecting men over fifty years of age, increasing in severity with increasing age. The symptoms of the condition include, but are not limited to, increased difficulty in urination and sexual dysfunction. These symptoms are induced by enlargement, or hyperplasia, of the prostate gland. As the prostate increases in size, it impinges on free-flow of fluids through the male urethra. Concommitantly, the increased noradrenergic innervation of the enlarged prostate leads to an increased adrenergic tone of the bladder neck and urethra, further restricting the flow of urine through the urethra.
Bladder outlet obstruction (BOO) in BPH patients results from a static component of increased prostatic mass which physically impinges on the urethra and a dynamic component of increased contractile tone of the prostatic-urethral smooth muscle. Standard treatment of BPH involves surgical or pharmacological intervention. Surgical intervention, either by removal of the prostate via radical prostatectomy or removing the prostatic adenoma via transurethral resection of the prostate alleviates both the static and dynamic components of BOO since the entire prostate or the majority of the prostatic smooth muscle is removed. Although these procedures result in the most marked improvement in symptoms, there is the possibility of mortality and morbidity since these are invasive surgical procedures. Many patients suffer incontinence and retrograde ejaculation as a consequence of these surgical procedures. Because of the chances for morbidity and mortality, these procedures are not optimum for patients with mild to moderate symptoms in a disease which is not life-threatening.
Pharmacological treatment with 5a-reductase inhibitors such as finasteride reduces the size of the prostate, thereby alleviating the static component of BOO. However, the symptomatic improvement following this therapy is significantly less than that following surgery. The lesser efficacy is likely mechanism-based in that 5a-reductase inhibitors decrease the size of the prostate by reducing the amount of epithelial tissue without affecting the smooth muscle, therefore the dynamic component of BOO may still be present.
Another pharmacological therapy involves the administration of subtype nonselective alpha-1 adrenergic receptor antagonists. These agents relax the prostatic-urethral smooth muscle by blocking endogenous sympathetic tone hence affecting the dynamic component of BOO. However, these agents were originally developed to treat hypertension and have effects on the cardiovascular system which include decreasing blood pressure and causing orthostatic hypotension. The efficacy of this therapy is also significantly less than that following surgery. Efficacy of these agents may be limited by dose-related cardiovascular side-effects, the remaining static component of BOO, and/or because another endogenus substance contributes to the dynamic prostatic-urethral tone.
The predominant alpha-1 adrenergic receptor subtype responsible for alpha 1 agonist mediated contraction of human prostatic-urethral smooth muscle is the alpha-1a subtype. Animal studies suggest that the alpha-1a receptor is not involved in normal blood pressure regulation, therefore selective alpha-1a receptor antagonists may not have the dose-limiting side-effects of subtype nonselective antagonists. The only other substances identified to potently contract human prostate tissue are endothelins (ET) via both the ET-A and ET-B receptors. Endothelin-1 is found in very high concentrations in the prostate and appears to be produced locally in the epithelial tissue in the prostate (Langenstroer, et al 1993 J. of Urology 149:495-99). Alpha adrenergic tone is known to be involved in the dynamic component of BPH based on the efficacy of the subtype nonselective compounds approved for clinical use. The role of ET in BPH is unknown at this time.
It is therefore an object of the invention to find an improved therapy for treating benign prostatic hyperplasia. It is a further object of the invention to find improved methods for relaxing lower urinary tract tissue in patients in need of such treatment. Still a further object of the present invention is to improve lower urinary tract symptoms which include increasing urine flow rate, decreasing residual urine volume and improving overall obstructive and irritative symptoms in patients with benign prostatic hyperplasia or symptomatic prostatism.
It has now been found that combination therapy with an alpha-1a antagonist and an endothelin antagonist, preferably a mixed ET-A/ET-B antagonist, is useful for treating benign prostatic hyperplasia, for relaxing lower urinary tract tissue, and for improving lower urinary tract symptoms which include increasing urine flow rate, decreasing residual urine volume and improving overall obstructive and irritative symptoms in patients with benign prostatic hyperplasia or symptomatic prostatism. The advantage of the combined administration of an alpha-1a antagonist and an ET-A/ET-B antagonist is that two putative components which determine the dynamic prostatic tone would be inhibited without the dose-limiting side-effects observed with subtype non selective alpha-1 antagonists.
The present invention provides a composition comprising an alpha-1a adrenergic receptor antagonist and an endothelin antagonist, and pharmaceutically acceptable salts thereof.
In one embodiment of the instant invention is the composition of an alpha-1a adrenergic receptor antagonist and an endothelin antagonist wherein the alpha-1a adrenergic receptor antagonist is a selective alpha-1a adrenergic receptor antagonist; and the pharmaceutically acceptable salts thereof.
In a class of the embodiment is the composition comprising a selective alpha-1a adrenergic receptor antagonist and an endothelin antagonist wherein the selective alpha-1a adrenergic receptor antagonist is selected from Compound A, Compound C, Compound D, Compound E, KMD-3213, tamsulosin, REC 15/2739 or A131701; and the pharmaceutically acceptable salts thereof.
In a subclass of the embodiment is the composition mentioned above wherein the selective alpha-1a adrenergic receptor antagonist is Compound A.
In another subclass of the embodiment is the composition mentioned above wherein the selective alpha-1a adrenergic receptor antagonist is Compound C.
In another subclass of the embodiment is the composition mentioned above wherein the selective alpha-1a adrenergic receptor antagonist is Compound D.
In another subclass of the embodiment is the composition mentioned above wherein the selective alpha-1a adrenergic receptor antagonist is Compound E.
In a second class of the embodiment is the composition comprising an alpha-1a adrenergic receptor antagonist and an endothelin antagonist wherein the endothelin antagonist is a subtype non-selective endothelin antagonist; and the pharmaceutically acceptable salts.
In a subclass of the second class of the embodiment is the composition wherein the subtype non-selective endothelin antagonist is selected from Compound B, bosentan, SB217242, SB209670, A 127722 or A 182086.
Illustrating the subclass is the composition wherein the subtype non-selective endothelin antagonist is Compound B.
Illustrating the embodiment is the composition comprising a selective alpha-1a adrenergic receptor antagonist and an endothelin antagonist wherein the selective alpha-1a adrenergic receptor antagonist is Compound A, Compound D, Compound E, or a pharmaceutically acceptable salt thereof; and the endothelin antagonist is Compound B or a pharmaceutically acceptable salt thereof.
Illustrating the embodiment is the composition comprising a selective alpha-1a adrenergic receptor antagonist and an endothelin antagonist wherein the selective alpha-1a adrenergic receptor antagonist is Compound A and the endothelin antagonist is Compound B; and pharmaceutically acceptable salts thereof.
Also illustrating the embodiment is the composition comprising a selective alpha-1a adrenergic receptor antagonist and an endothelin antagonist wherein the selective alpha-1a adrenergic receptor antagonist is Compound D and the endothelin antagonist is Compound B; and pharmaceutically acceptable salts thereof.
Also illustrating the embodiment is the composition comprising a selective alpha-1a adrenergic receptor antagonist and an endothelin antagonist wherein the selective alpha-1a adrenergic receptor antagonist is Compound E and the endothelin antagonist is Compound B; and pharmaceutically acceptable salts thereof.
Further illustrating the embodiment is the composition comprising an alpha-1a adrenergic receptor antagonist, an endothelin antagonist, a 5a-reductase inhibitor, and pharmaceutically acceptable salts thereof.
A second embodiment of the invention is a method of treating benign prostatic hyperplasia in a subject in need thereof which comprises administering to the subject an effective amount of an alpha-1a antagonist, an endothelin antagonist, and optionally a 5a-reductase inhibitor.
A class of the second embodiment is the method wherein the alpha-1a adrenergic receptor antagonist is selected from Compound A, Compound D, Compound E, KMD-3213, tamsulosin, REC 15/2739, A131701, or pharmaceutically acceptable salts thereof; and the endothelin antagonist is selected from Compound B, bosentan, SB217242, SB209670, A 127722, A 182086, or pharmaceutically acceptable salts thereof.
A subclass of the second embodiment is the method wherein the alpha-1a adrenergic receptor antagonist is Compound D or a pharmaceutically acceptable salt thereof, and the endothelin antagonist is Compound B or a pharmaceutically acceptable salt thereof
Another subclass of the second embodiment is the method wherein the alpha-1a adrenergic receptor antagonist is Compound E or a pharmaceutically acceptable salt thereof, and the endothelin antagonist is Compound B or a pharmaceutically acceptable salt thereof.
Another class of the second embodiment is the method wherein the alpha-1a adrenergic receptor antagonist is selected from Compound A, Compound C, KMD-3213, tamsulosin, REC 15/2739 or A131701 and the endothelin antagonist is selected from Compound B, bosentan, SB217242, SB209670, A 127722 or A 182086.
A subclass of the second embodiment is the method wherein the alpha-1a adrenergic receptor antagonist is Compound A and the endothelin antagonist is Compound B.
Another subclass of the second embodiment is the method wherein the alpha-1a adrenergic receptor antagonist is Compound C and the endothelin antagonist is Compound B.
A third embodiment of the instant invention is a method of relaxing lower urinary tract tissue in a subject in need thereof which comprises administering to the subject an effective amount of an alpha-1a antagonist, an endothelin antagonist, and optionally a 5a-reductase inhibitor.
A class of the third embodiment is the method wherein the alpha-1a adrenergic receptor antagonist is selected from Compound A, Compound D, Compound E, KMD-3213, tamsulosin, REC 15/2739, A131701, or pharmaceutically acceptable salts thereof; and the endothelin antagonist is selected from Compound B, bosentan, SB217242, SB209670, A 127722, A 182086, or pharmaceutically acceptable salts thereof.
A subclass of the third embodiment is the method wherein the alpha-1a adrenergic receptor antagonist is Compound D or a pharmaceutically acceptable salt thereof, and the endothelin antagonist is Compound B or a pharmaceutically acceptable salt thereof.
Another subclass of the third embodiment is the method wherein the alpha-1a adrenergic receptor antagonist is Compound E or a pharmaceutically acceptable salt thereof, and the endothelin antagonist is Compound B or a pharmaceutically acceptable salt thereof.
Another class of the third embodiment is the method wherein the alpha-1a adrenergic receptor antagonist is selected from Compound A, Compound C, KMD-3213, tamsulosin, REC 15/2739 or A131701 and the endothelin antagonist is selected from Compound B, bosentan, SB217242, SB209670, A 127722 or A 182086.
A subclass of the third embodiment is the method wherein the alpha-1a adrenergic receptor antagonist is Compound A and the endothelin antagonist is Compound B.
In another subclass of the third embodiment is the method wherein the alpha-1a adrenergic receptor antagonist is Compound C and the endothelin antagonist is Compound B.
A fourth embodiment of the invention is a method of improving lower urinary tract symptoms in a benign prostatic hyperplasia patient which comprises administering to the subject an effective amount of an alpha-1a antagonist, an endothelin antagonist, and optionally a 5a-reductase inhibitor.
A class of the fourth embodiment is method for increasing urine flow rate.
A second class of the fourth embodiment is the method for decreasing residual urine volume.
A third class of the fourth embodiment is a method of improving lower urinary tract symptoms in a benign prostatic hyperplasia patient which comprises administering to the subject an effective amount of an alpha-1a antagonist, an endothelin antagonist, and optionally a 5a-reductase inhibitor wherein the alpha-1a adrenergic receptor antagonist is selected from Compound A, Compound C, KMD-3213, tamsulosin, REC 15/2739 or A131701 and the endothelin antagonist is selected from Compound B, bosentan, SB217242, SB209670, A 127722 or A 182086.
A fourth class of the fourth embodiment is a method of improving lower urinary tract symptoms in a benign prostatic hyperplasia patient which comprises administering to the subject an effective amount of an alpha-1a antagonist, an endothelin antagonist, and optionally a 5a-reductase inhibitor wherein the alpha-1a adrenergic receptor antagonist is selected from Compound A, Compound D, Compound E, KMD-3213, tamsulosin, REC 15/2739, A131701, or pharmaceutically acceptable salts thereof; and the endothelin antagonist is selected from Compound B, bosentan, SB217242, SB209670, A 127722, A 182086, or pharmaceutically acceptable salts thereof.
A subclass of the fourth embodiment is the method wherein the alpha-1a adrenergic receptor antagonist is Compound A and the endothelin antagonist is Compound B.
Another subclass of the fourth embodiment is the method wherein the alpha-1a adrenergic receptor antagonist is Compound C and the endothelin antagonist is Compound B.
Still another subclass of the fourth embodiment is the method wherein the alpha-1a adrenergic receptor antagonist is Compound D or a pharmaceutically acceptable salt thereof, and the endothelin antagonist is Compound B or a pharmaceutically acceptable salt thereof.
Still another subclass of the fourth embodiment is the method wherein the alpha-1a adrenergic receptor antagonist is Compound E or a pharmaceutically acceptable salt thereof, and the endothelin antagonist is Compound B or a pharmaceutically acceptable salt thereof.
A fifth embodiment of the invention is a pharmaceutical composition comprising an alpha-1a adrenergic receptor antagonist and an endothelin antagonist, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
A class of the fifth embodiment is a pharmaceutical composition comprising an alpha-1a adrenergic receptor antagonist and an endothelin antagonist, wherein the alpha-1a adrenergic receptor antagonist is Compound A and the endothelin antagonist is Compound B, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
Another class of the fifth embodiment is a pharmaceutical composition comprising an alpha-1a adrenergic receptor antagonist and an endothelin antagonist, wherein the alpha-1a adrenergic receptor antagonist is Compound C and the endothelin antagonist is Compound B, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
Another class of the fifth embodiment is a pharmaceutical composition comprising an alpha-1a adrenergic receptor antagonist and an endothelin antagonist, wherein the alpha-1a adrenergic receptor antagonist is Compound D and the endothelin antagonist is Compound B, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
Another class of the fifth embodiment is a pharmaceutical composition comprising an alpha-1a adrenergic receptor antagonist and an endothelin antagonist, wherein the alpha-1a adrenergic receptor antagonist is Compound E and the endothelin antagonist is Compound B, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
Exemplifying the invention is a pharmaceutical composition made by combining an alpha-1a antagonist, an endothelin antagonist, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
Further exemplifying the invention is a process for making a pharmaceutical composition comprising combining an alpha-1a antagonist, an endothelin antagonist, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
This invention relates to combination therapy for the treatment of benign prostatic hyperplasia comprising an alpha-1a antagonist and an endothelin antagonist. More specifically he use of a selective alpha-1a adrenergic receptor antagonist in combination with a subtype non-selective endothelin antagonist, and optionally a 5a-reductase inhibitor (e.g., finasteride), provides relief of lower urinary tract symptoms in patients with symptomatic prostatism or benign prostatic hyperplasia. This combination therapy improves lower urinary tract symptoms including increasing urine flow rate, decreasing residual urine volume and improving overall obstructive and irritative symptoms in patients with benign prostatic hyperplasia or symptomatic prostatism. The combinations of the present invention result in improvement of symptoms associated with BPH by blocking endogenous noradrenergic and endothelin-mediated smooth muscle contraction of the smooth muscle in the lower urinary tract including the prostate, urethra, bladder neck and detrusor to reduce bladder outlet obstruction, improve bladder compliance, and/or decrease detrusor instability.
For use in medicine, the salts of the compounds of this invention refer to non-toxic xe2x80x9cpharmaceutically acceptable salts.xe2x80x9d Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
The instant invention includes the combination wherein all of the individual components are in the form of pharmaceutically acceptable salts and the combination wherein one or more of the individual components is in the form of a pharmaceutically acceptable salt while other of the components are used as the free base.
Recently, a number of alpha-1a adrenergic receptor antagonist compounds have been disclosed as being useful in the treatment of BPH. These alpha-1a adrenergic receptor antagonists and their utility in treating BPH and inhibiting contraction of lower urinary tract tissue are described in PCT International Application Publication No. WO 96/14846, published May 23, 1996. More particularly, the compound (+)-5-Methoxycarbonyl-6-(3,4-difluorophenyl-4-methoxymethyl-1-{N-[3-(4-(2-pyridyl)piperdin-1-yl)propyl]}-carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine, disclosed in Example 30 of WO 96/14846, and-referred to herein as xe2x80x9cCompound A,xe2x80x9d is a potent and selective antagonist of the alpha-1a adrenergic receptor antagonist and is useful in the treatment of BPH. 
Compound A is prepared according to the procedure of Example 30 in WO 96/14846 or according to the processes disclosed in detail herein. The identification of Compound A as an alpha-1a adrenergic receptor antagonist was established according to the assays described in WO 96/14846.
Compound A, and pharmaceutically acceptable salts thereof exhibit high selectivity for the human alpha-1a adrenergic receptor. One implication of this selectivity is that these compounds display selectivity for lowering intraurethral pressure without substantially affecting diastolic blood pressure.
The term xe2x80x9cCompound Cxe2x80x9d as used herein is trans(+)-4-(3,4-Difluorophenyl)-5-methyl-2-oxo-oxazolidine-3-carboxylic acid {3-[4-(4-fluorophenyl)-piperidin-1-yl]propyl}amide, a potent and selective antagonist of the alpha-1a adrenergic receptor antagonist useful in the treatment of BPH. 
Compound C is prepared according to the procedures described herein.
The term xe2x80x9cCompound Dxe2x80x9d as used herein is (xe2x88x92)-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid {3-[4-(4-fluorophenyl)-piperidin-1-yl]-propyl}-amide. Compound D is a potent and selective antagonist of the alpha-1a adrenergic receptor antagonist useful in the treatment of BPH. 
Compound D can be prepared as described below.
The term xe2x80x9cCompound Exe2x80x9d as used herein is (4S)trans-4-(3,4-difluorophenyl)-3-[1-(4-pyridin-2-yl-cyclohexyl)-(3R)-pyrrolidin-3-ylcarbamoyl]-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester. 
Compound E is a potent and selective antagonist of the alpha-1a adrenergic receptor antagonist useful in the treatment of BPH. Compound E is disclosed in WO 98/57641 and can be prepared in accordance with the procedure of Example 48 in WO 98/57641.
KMD-3213 is 1-(3-Hydroxypropyl)-5-[2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]indoline-7-carboxamide. 
KMD-3213 is useful in the treatment of dysuria and can be prepared according to the procedures contained in U.S. Pat. No. 5,387,603 which issued, Feb. 7, 1995.
Tamsulosin is (R)-5-[2-[[2-(2-Ethoxyphenoxy) ethyl]amino]propyl]-2-methoxybenzenesulfonamide monohydrochloride, also known as tamsulosin hydrochloride, LY253351, R-(xe2x88x92)-YM-12617, YM-12617-1, YM617, and FLOMAX(copyright). 
Tamsulosin is an alpha 1-a adrenergic receptor antagonist and can be prepared according to the procedures outlined in U.S. Pat. No. 4,703,063.
REC 15/2739 is N-[3-[4-(2-Methoxyphenyl1-piperazinyl]propyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxamide, also known as Recordati 15/2739 or SB 216469. 
REC 15/2739 is an alpha 1-a adrenergic receptor antagonist and can be prepared according to the procedures described in U.S. Pat. No. 5,403,842 which issued on Apr. 4, 1995.
A131701 is (3aR-cis)-3-[2-(1,3,3a,4,5,9b-hexahydro-6-methoxy-2H-benz[e]isoindol-2-yl)ethyl]-pyrido[2xe2x80x2,3xe2x80x2:4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione. 
A131701 is an alpha 1-a adrenergic receptor antagonist and can be prepared according to the procedures outlined in U.S. Pat. No. 5,597,823 which issued on Jan. 28, 1997.
A number of endothelin antagonists have been disclosed as useful for inhibiting vasoconstriction. This antagonism can be helpful in alleviating the symptoms of BPH. These endothelin antagonists and their utility as inhibitors of vasoconstriction are described in U.S. Pat. No. 5,389,629, which issued on Feb. 14, 1995. More particularly, BQ-4508-2 disclosed in U.S. Pat. No. 5,389,620, and referred to herein as xe2x80x9cCompound B,xe2x80x9d is a potent subtype non-selective endothelin antagonist. 
Compound B can be prepared according to the procedures described in U.S. Pat. No. 5,389,620 or according to the process disclosed herein.
Compound B and the pharmaceutically acceptable salts thereof inhibit endothelin, which induces sustained contraction of either vascular or non-vascular smooth muscle. By inhibiting endothelin, Compound B can effect a relaxation of smooth muscle tissue and prove helpful in treating BPH.
Bosentan is p-tert-Butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide monohydrate, also known as Ro-47-0203/029. 
Bosentan is an endothelin antagonist and can be prepared according to the procedures described in U.S. Pat. No. 5,292,740 which issued Mar. 8, 1994.
SB217242 is [1S-(1.alpha.,2.beta.,3.alpha.)]-1-(1,3-benzodioxol-5-yl)-2,3-dihydro-3-[2-(2-hydroxyethoxy)-4-methoxyphenyl]-5-propoxy-1H-Indene-2-carboxylic acid. 
SB217242 is an endothelin antagonist and can prepared according to the procedures described in WO 94/25013 which published on Nov. 10, 1994.
SB209670 is [1S-(1.alpha.,2.beta.,3.alpha.)]-1-(1,3-benzodioxol-5-yl)-3-[2-(carbomethoxy)-4-methoxyphenyl]-2,3,-dihydro-5-propoxy-1H-Indene-2-carboxylic acid. 
SB209670 is an endothelin antagonist and can be prepared according to the procedures described in WO 94/25013 which published on Nov. 10, 1994.
A 127722 is (2.alpha.,3.beta.,4.alpha.)-4-(1,3-Benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)3-pyrrolidinecarboxylic acid. 
A 127722 is an endothelin antagonist and can be prepared according to the procedures outlined in WO 96/06095 which published on Feb. 29, 1996.
A 182086 is [2R-(2.alpha.,3.beta.,4.alpha.)]-4-(1,3-Benzodioxol-5-yl)-2-(3-fluro-4-methoxyphenyl)-1-[2-[(pentylsulfonyl)propylamino]ethyl]-3-pyrrolidinecarboxylic acid. 
A 182086 is an endothelin antagonist and can be prepared according to the procedures outlined in WO 97/30045 which published on Aug. 21, 1997.
For the utility employed herein, the end product compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.
These pharmaceutical compositions may be in the form of orally-administrable suspensions or tablets; nasal sprays; sterile injectable preparations, for example, as sterile injectable aqueous or oleaginous suspensions or suppositories.
In accordance with the method of the present invention, the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. For example, in a two-component combination including Compound A and Compound B, treatment with Compound B can commence prior to, subsequent to or concurrent with commencement of treatment with Compound A. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term xe2x80x9cadministeringxe2x80x9d is to be interpreted accordingly.
When administered orally as a suspension, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners/flavoring agents known in the art. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
The injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer""s solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquidify and/or dissolve in the rectal cavity to release the drug.
The alpha-1a antagonists may be employed in the present invention over a dosage range of from about 0.01 mg per subject to about 500 mg per subject. More particularly the effective amount of alpha-1a compound is about 0.1 mg to about 60 mg and in a subclass 1 mg to about 20 mg. One exemplification of this subclass ranges from 5 mg to about 20 mg with specific example of 10, 12.5 and 15 mg.
The endothelin antagonists may be employed in the instant invention over a dosage range of from about 0.1 to 750 mg. More particularly the dosage will vary from about 0.1 to about 100 mg and for the more potent compounds from 0.1 to about 2 mg.
Optionally the composition or method of the instant invention, employs a 5 alpha reductase inhibitor e.g., finasteride. A suitable dosage range for this 5 alpha reductase inhibitor is 1 mg to 10 mg exemplified by 5 mg. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
The term xe2x80x9cCompound A,xe2x80x9d as used herein refers to the free base shown below: 
Compound A and its utility for antagonizing the alpha-1a adrenergic receptor, for treating BPH and for inhibiting lower urinary tract tissue is described in detail in WO 96/14846. Compound A is readily prepared according to the procedure of Example 30 in WO 96/14846, or according to the processes disclosed herein.
The term xe2x80x9cselective alpha-1a adrenergic receptor antagonist,xe2x80x9d as used herein, refers to an alpha-1a antagonist compound which is at least ten fold selective for the human alpha-1a adrenergic receptor as compared to the human alpha 1b, alpha 1d, alpha 2a, alpha 2b and alpha 2c adrenergic receptors. Methods of identification of selective alpha-1a receptor antagonists are disclosed in U.S. Pat. No. 5,403,847 which issued on Apr. 4, 1995.
The term xe2x80x9clower urinary tract tissue,xe2x80x9d as used herein, refers to and includes, but is not limited to, prostatic smooth muscle, the prostatic capsule, the urethra and the bladder neck.
The term xe2x80x9cimproving lower urinary tract symptomsxe2x80x9d as used herein includes increasing urine flow rate, decreasing residual urine volume and improving overall obstructive and irritative symptoms in patients with benign prostatic hyperplasia or symptomatic prostatism.
The term xe2x80x9csubject,xe2x80x9d as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated. Since the instant invention refers to compositions comprising two or more agents, the xe2x80x9ctherapeutically effective amountxe2x80x9d is that amount of the combination of the agents taken together so that the combined effect elicits the desired biological or medicinal response. For example, the therapeutically effective amount of a composition comprising Compound A and Compound B would be the amount of Compound A and the amount of Compound B that when taken together have a combined effect that is therapeutically effective.
As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
Abbreviations used in the instant specification, particularly the Schemes and Examples, are as follows:
Aq=aqueous
Ac=acetyl
CDI=carbonyl diimidazole
DMF=N,N-dimethylformamide
DMSO=dimethylsulfoxide
EDC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
EtOAc=ethyl acetate
EtOH=ethanol
HOAt=1-hydroxy-7-azabenzotriazole
IPAc=isopropyl acetate
LDA=lithium diisopropylamide
Me=methyl
MeOH=methanol
MTBE=methyl tert-butyl ether
t-Bu=tertiary -butyl or tert-butyl
THF=tetrahydrofuran
The end product Compound A L-tartrate salt, i.e., (+)-5-Methoxycarbonyl-6-(3,4-difluorophenyl)-4-methoxy-carbonyl-1-{N-[3-(4-(2-pyridyl)piperidin-1-yl)propyl]}-carboxamido-1,2,3,6-tetrahydro-2-oxopyrimidine L-tartrate salt, (1) may be prepared according to Scheme 1. Racemic 2 is readily prepared from commercially available 3,4-difluorobenzaldehyde, methyl 4-methoxyacetoacetate, and urea following the teaching of PCT International Application Publication No. WO 97/21687, published Jun. 19, 1997. Enantiomeric resolution to afford (+)-2 may be accomplished by conventional techniques known to those skilled in the art, or by removing (xe2x88x92)-2 via ester hydrolysis with commercially available protease enzyme, for example, Subtilisin. (+)-2 is coupled with 3-[4-(2-pyridyl)piperidin-1-yl]propylamine, (6) (Scheme 3), utilizing carbonyl diimidazole, to afford (+)-5-methoxycarbonyl-6-(3,4-difluorophenyl)-4-methoxycarbonyl-1-{N-[3-(4-(2-pyridyl)piperidin-1-yl)propyl]} carboxamido-1,2,3,6-tetrahydro-2-oxopyrimidine, (3). Crystallization of the (+)-5-methoxycarbonyl-6-(3,4-difluorophenyl)-4-methoxycarbonyl-1-{N-[3-(4-(2-pyridyl)piperidin-1-yl)propyl]}carboxamido-1,2,3,6-tetrahydro-2-oxopyrimidine L-tartrate salt, (1) is accomplished by treating a solution of 3 with L-tartaric acid. 
3-[4-(2-pyridyl)piperidin-1-yl]propylamine, (6) can be prepared following the teachings of WO 96/14846, or by the procedure outlined in Scheme 2 wherein commercially available 2,4xe2x80x2-dipyridyl is alkylated with 3-bromopropylamine hydrobromide to afford pyridinium salt 4. Reduction of 4 with sodium borohydride affords 5 which is hydrogenated over Pearlman""s catalyst to afford 3-[4-(2-pyridyl)piperidin-1-yl]propylamine, (6). If desired, 6 may be used directly in the preparation of 3, or it may be crystallized as its L-tartrate salt 7. 